Tovorafenib for Treatment of Craniopharyngioma in Children and Young Adults

Inclusion Criteria:

Newly Diagnosed Participants:

• Newly diagnosed craniopharyngioma, as based on imaging characteristics and centralradiology review. Participants will initially be screened within confines of ascreening consent and only those participants with findings consistent withcraniopharyngioma and without findings suggesting an indeterminate lesion or lesionof an alternative diagnosis (including abnormal tumor markers found in blood orcerebral spinal fluid (CSF), if completed as part of standard of care (SOC) work-upor if lesion concerning for alternate diagnosis) will move ahead with enrollment onthe treatment protocol. Additionally, for participants that have undergone initialbiopsy to confirm diagnosis, are within 6 weeks of radiographic diagnosis, and areplanned to undergo follow up second surgery for additional tumor resection as perstandard of care recommendations, these participants will also be consideredeligible.

• Participants must be surgical candidates for biopsy or resection and planned forstandard of care biopsy or resection.

Recurrent Participants:

• Recurrent craniopharyngioma, as based on histologic confirmation at time of initialdiagnosis (participants with Adamantinomatous craniopharyngioma (ACP) will only beeligible for the recurrent arm).

• Recurrent craniopharyngioma without prior histologic confirmation will initially bescreened within confines of a screening consent and only those participants withfindings consistent with craniopharyngioma and without findings suggesting anindeterminate lesion or lesion of an alternative diagnosis (including abnormal tumormarkers found in blood or CSF, if completed as part of SOC work-up or if lesionconcerning for alternate diagnosis) will move ahead with enrollment on the treatmentprotocol.

• Participants should be surgical candidates for biopsy or resection. If participantsare not surgical candidates, but have available archival tumor tissue, they will beenrolled into the exploratory cohort.

• Participants must be willing to provide archival tissue, a minimum of 10-20 paraffinembedded unstained slides OR 1 block with tumor content of 40% or greater isrequired. Participants who do not meet this criteria may be discussed on acase-by-case basis with the Study Chair(s).

• Participants can have been previously treated with surgical resection alone, cystdrainage and biopsy alone, radiation therapy, other systemic therapies, or anycombination thereof.

• Prior Therapy:

• Had their last dose of myelosuppressive chemotherapy >= 21 days prior to studyregistration (>=42 days if nitrosourea therapy).

• Had their last dose of hematopoietic growth factor >=14 days (long-actinggrowth factor) or >=7 days (short-acting growth factor) prior to studyregistration, or beyond the time during which adverse events (AEs) are known tooccur.

• Had their last dose of biologic (anti-neoplastic agent) >=7 days prior to studyregistration, or beyond the time during which AEs are known to occur.

• Had their last dose of monoclonal antibodies >=21 days prior to studyregistration.

Radiation:

• Had their last fraction of local irradiation to primary tumor >=12 weeks prior toregistration; investigators are reminded to review potentially eligible cases toavoid confusion with pseudo-progression.

• At least 14 days after local palliative radiation (small-port).

All Participants:

• Age 1 to 39 years.

• Participants continuing on maintenance therapy after standard of carebiopsy/resection must have measurable disease, as defined as lesions that can beaccurately measured in two dimensions (longest diameter to be recorded) with aminimum size of no less than double the slice thickness. Previously irradiatedlesions are considered non-measurable except in cases of documented progression ofthe lesion since the completion of radiation therapy. Participants withoutmeasurable disease may continue on study and will be followed for study endpoints,but will not be included as part of target accrual.

• Performance Score: Karnofsky >= 50 for participants > 16 years of age and Lansky >= 50 for participants <= 16 years of age. Participants who are unable to walk becauseof paralysis, but who are up in a wheelchair, will be considered ambulatory for thepurpose of assessing the performance score.

• Corticosteroids: Participants who are receiving dexamethasone must be on a stable ordecreasing dose for at least 1 week prior to registration. The participant steroiddose should be no more than a steroid-equivalent of dexamethasone 0.1 mg/kg/day (ormaximum 4mg/day; whichever is the lower dose) at time of enrollment. Participantsthat have been stable on physiologic hormone replacement for hypopituitarism areallowed.

• Organ Function Requirements:

• Adequate Bone Marrow Function defined as:

• Peripheral absolute neutrophil count (ANC) >=1000/mm3.

• Platelet count >= 100,000/mm3 (transfusion independent, defined as notreceiving platelet transfusions for at least 7 days prior to enrollment).

• Adequate Renal Function defined as- ---A serum creatinine < 1.5 Upper Limit normal (ULN) based on age and gender.

• Adequate Liver Function defined as-

• Bilirubin (sum of conjugated + unconjugated) <= 1.5 x upper limit ofnormal (ULN) for age (except in participants with documented Gilbertsyndrome).

• Serum glutamic-pyruvic transaminase (SGPT)((alanine aminotransferase (ALT)) <= 3 x ULN.

• Serum albumin >=2 g/dL (20g/L).

• Adequate Neurologic Function defined as participants with seizure disorder maybe enrolled if well controlled. Participants on non-enzyme inducinganticonvulsants may be excluded pending interaction(s) with study drug.

• Adequate Pulmonary Function defined as no evidence of dyspnea at rest, noexercise intolerance due to pulmonary insufficiency, and a pulse oximetry of > 92% while breathing room air.

• prothrombin time (PT) /partial thromboplastin time (PTT)/InternationalNormalized Ratio (INR) within institutional normal limits or deemed appropriatefor surgical intervention by the treating team for patients undergoing surgerybiopsy/resection

• The effects of Tovorafenib on the developing human fetus are unknown. For thisreason, women of child-bearing potential and men must agree to use adequatecontraception (non-hormonal contraception; barrier method of birth control;abstinence - note, tovorafenib can make hormonal contraceptives ineffective) priorto study entry, for the duration of study participation and 28 days after completionof Tovorafenib administration, whichever is later. Should a woman become pregnant orsuspect she is pregnant while she or her partner is participating in this study, sheshould inform her treating physician immediately.

• A legal parent/guardian or participants must be able to understand, and willing tosign, a written informed consent and assent document, as appropriate.

• Ability to complete the PedsQL Core Module. Patients must enroll on PNOC COMP ifPNOC COMP is open to accrual at the enrolling institution.

Exclusion Criteria:

Newly Diagnosed Participants:

• Participants should not have undergone any previous tumor-directed therapy.

Recurrent Participants:

• Participants who have had chemotherapy or radiotherapy within 3 weeks (6 weeks fornitrosoureas or mitomycin C) prior to entering the study or those who have notrecovered from acute adverse events due to agents administered more than 4 weeksearlier.

• Participants must be at least 1 week since the completion of therapy with a biologicor small molecule agent. For any agent with known adverse events that can occurbeyond 1 week after administration, the period prior to enrollment must be beyondthe time during which adverse events are known to occur. Such participants shouldalso be discussed with study chairs.

• Participants should not have previously received any RAS-pathway, but have notreceived Tovorafenib will be eligible.

All Participants:

• Rapidly progressive symptoms that require urgent surgery or radiation therapy, whichwould prevent central review and or preclude participation with tumor-directedmedical management alone.

• Uncontrolled symptoms of neuroendocrine dysfunction such as diabetes insipidus,hypothyroidism, panhypopituitarism (participants can be on supplemental medicationsfor hormonal repletion; however, should be on controlled doses for at least 2 weeksprior to enrollment).

• Clinically significant active cardiovascular disease, or history of myocardialinfarction, or deep vein thrombosis/pulmonary embolism within 6 months prior toregistration, ongoing cardiomyopathy, or current prolonged QT interval corrected forheart rate by Fridericia's formula (QTcF) interval > 440 ms based on triplicate ECGaverage.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to Tovorafenib or other agents used in study.

• Nausea and vomiting >= Grade 2, malabsorption requiring supplementation, orsignificant bowel or stomach resection that would preclude adequate absorption.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection.

• Participants who are receiving any other investigational agents.

• Women of childbearing potential must not be pregnant or breast-feeding.

• Current treatment with a strong cytochrome P4502C8(CYP2C8) inhibitor or inducerother than those allowed per Section 5.6.1. Medications that are substrates ofCYP2C8 are allowed but should be used with caution.

• Participants with inability to return for follow-up visits or obtain follow-upstudies required to assess toxicity to therapy.